Glycosaminoglycan chains on cell surface proteoglycans serve as receptors for the binding of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) to cells. Binding is not sufficient for entry, however: other cell surface components are necessary for virus entry, which occurs by fusion of the virion envelope with a cell membrane. For example, Chinese hamster ovary (CHO) cells express glycosaminoglycan chains to which HSV-1 and HSV-2 can bind, but are resistant to the entry of some HSV strains, particularly HSV-1(KOS).
The present invention is directed to a newly discovered protein that enables herpes simplex virus (HSV) to penetrate into cells and is a previously undiscovered member of the family of receptors designated the tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family. Members of this family have characteristic repeats of amino acid sequence containing multiple cysteines and serve as receptors for a variety of specific ligands, including but not limited to cytokines. The protein is designated herpes virus entry receptor protein or HVEM.
By identifying the gene that encodes HVEM, by showing that HVEM can mediate the entry of HSV into cells and by performing experiments to define viral and cell factors that influence the ability of HVEM to mediate HSV entry, the inventors have provided the knowledge and biological material required (i) to develop antiviral drugs that can act to block HSV (and perhaps other herpesvirus) entry into cells; (ii) to identify other members of the TNFR/NGFR family (or other cell surface molecules) that can serve as receptors for HSV-1, HSV-2 or other herpesviruses; (iii) to identify the natural ligand for the receptor; and (iv) to develop therapeutic approaches for enhancing or inhibiting action of the ligand on the receptor, depending on the pathologic or beneficial consequences of this action.